Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
Cell Rep. 2018 Mar 6;22(10):2628-2641. doi: 10.1016/j.celrep.2018.02.048.
Monocytes and dendritic cells (DCs), mononuclear phagocytes essential for immune responses, develop from hematopoietic stem cells via monocyte-DC progenitors (MDPs). The molecular basis of their development remains unclear. Because promoter-distal enhancers are key to cell fate decisions, we analyzed enhancer landscapes during mononuclear phagocyte development in vivo. Monocyte- and DC-specific enhancers were gradually established at progenitor stages before the expression of associated genes. Of the transcription factors predicted to bind to these enhancers, IRF8, essential for monocyte and DC development, was found to be required for the establishment of these enhancers, particularly those common to both monocyte and DC lineages. Although Irf8 mononuclear phagocyte progenitors, including MDPs, displayed grossly normal gene expression patterns, their enhancer landscapes resembled that of an upstream progenitor population. Our results illustrate the dynamic process by which key transcription factors regulate enhancer formation and, therefore, direct future gene expression to achieve mononuclear phagocyte development.
单核细胞和树突状细胞（DC）是免疫反应所必需的单核吞噬细胞，它们由造血干细胞通过单核细胞-树突状细胞前体（MDP）发育而来。它们的发育分子基础尚不清楚。因为启动子远端增强子是细胞命运决定的关键，所以我们分析了体内单核吞噬细胞发育过程中的增强子景观。单核细胞和 DC 特异性增强子在相关基因表达之前，在祖细胞阶段逐渐建立。预测与这些增强子结合的转录因子中，IRF8 对于单核细胞和 DC 的发育至关重要，发现其对于这些增强子的建立是必需的，特别是那些在单核细胞和 DC 谱系中共同的增强子。虽然 Irf8 单核吞噬细胞祖细胞，包括 MDP，表现出明显正常的基因表达模式，但它们的增强子景观类似于上游祖细胞群体。我们的研究结果说明了关键转录因子调节增强子形成的动态过程，从而指导未来的基因表达，以实现单核吞噬细胞的发育。
